The about 100 pharmacologically different products available for oral contraception are based on synthetic hormones, mostly as a fixed combination of an estrogen and a progestogen. The contraceptive action of these products is mediated principally via inhibition of ovulation, an effect mediated via specific macromolecular receptors. Evidence clearly shows the presence in human tissues of an estradiol-receptor, which does not bind progesterone, and of a progesterone-receptor which does not bind estrogens.
The synthetic hormones used as contraceptives act on the estradiol and progesterone target tissues. It is clear that the natural hormones, estradiol and progesterone, if delivered to the receptors, should bring the same contraceptive effect as the synthetic analogs, while possibly decreasing or eliminating the side effects accompanying the use of the current contraceptive formulations.
The estrogenic component used in the oral contraceptives (17 .alpha.-ethynyl estradiol or its 3-methyl ether) are admittedly responsible for thromboembolic phenomena, liver disturbances and impairment of carbohydrate metabolism. Although estradiol itself might induce abnormalities in liver function, the 17 .alpha.-ethynyl group certainly has additional effects.
Potency estimates of the various natural and synthetic sex hormones are generally obscured by the lack or inadequacy of the bioavailability and physiological availability studies. More detailed studies have been carried out only with the synthetic hormones used, although good bioavailability of estradiol from solution or in micronized forms has also been shown.
On the other hand, good bioavailability still does not necessarily mean high biological activity. Practically completely available (i.e., delivered to the bloodstream) drugs can have low physiological availability if they undergo conjugation and/or metabolism during the absorption process or during the first pass through the liver. These kinds of deactivation are expected to occur the fastest with natural substances, such as the natural sex hormones.
Indeed, inactivation of the natural estrogens in the intestines and in the liver occurs at such a rate that their oral efficacy is minimal as compared to the synthetic estrogens or when estradiol is administered parenterally.
The situation is quite similar in the case of progesterone, which undergoes fast and extensive metabolism in the liver after it is absorbed, the main metabolic pathway being the reduction of the .alpha.,.beta.-unsaturated ketone and the 20-oxo group to pregnane-3.alpha., 20-diol.
Both progesterone and estradiol are quite water insoluble substances. Thus, in order to deliver these natural hormones efficiently to the receptors, after oral administration, one has to solve two problems simultaneously:
Although various formulation techniques (deliver in solution, micronization, dilution with matrices, etc.) or physical-chemical approaches for increasing water solubility (complex formation), can certainly solve the first problem, to assure dissolution of the material, and consequently good absorption, but the major problem of fast deactivation of the active compounds cannot be influenced by such techniques.